There is growing evidence that psychosocial factors, such as stress and depression, may have a harmful impact on the outcome of a variety of diseases, such as cancer and heart disease. Although there is evidence that stress and depression may impair cellular immunity, the clinical relevance of these alterations has not been established in human immunodeficiency virus type-1 (HIV- 1) infection. In general, life stress, stress hormones, and cellular immunity have not been evaluated comprehensively in longitudinal HIV infected cohorts. Our data from up to 7.5 years of study in a cohort of HIV infected gay men (UNC Cohort) has provided clear evidence that psychosocial factors, such as life event stress, social support, coping style and depressive symptoms, may have a deleterious effect on both immunity and disease progression in early to mid stage HIV-l infection. In this resubmission, we will continue to expand our understanding of these complex psychosocial and neurobiological factors and their potential influence on HIV pathogenesis. In response to the SRG review, the goals of the revised research plan are: 1) To extend our initial findings on the deleterious effects of stress and depressive symptoms in early HIV disease in a rural cohort of gay men (UNC Cohort, HIV+ men only) in order to understand whether these relationships continue to influence the course of late HIV disease and mortality; and, 2) to establish a new, more heterogeneous urban sample (PENN Cohort) in order to relate our earlier findings to the demographics of today's HIV epidemic and to explore the impact of contemporary, highly active, antiretroviral therapies (HAART) and medication adherence on the stress and disease relationship. Building on the recognized methodological strengths and experience gained over a 10-year longitudinal cohort study, this revised proposal will address unanswered questions about the long-term role of life stress, depression, social support and coping in two critical contexts: early HIV disease in a diverse urban setting and late HIV disease in an established and well-characterized cohort, during a time when new therapies are emerging. This important and timely study also may provide new information on stress/endocrine/immune mechanisms that could be used to determine whether new pharmacotherapies (CRF-antagonists, glucocorticoid antagonists, substance P antagonists) might benefit HIV-infected populations and extend survival with HIV infection.